Crystalline form of 1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranoside, a method for its preparation and the use thereof for preparing medicaments

ABSTRACT

The invention relates to a crystalline form of 1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranoside, to a method for the preparation thereof, as well as to the use thereof for preparing medicaments.

The invention relates to a crystalline form of1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranoside,to pharmaceutical compositions and to uses of said crystalline form inthe therapeutic treatment or prevention. Furthermore the presentinvention relates to methods for the preparation of such a crystallineform.

BACKGROUND OF THE INVENTION

The compound1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranosideof the formula I

(in the following referred to it as “compound of the formula I”) isdescribed in the European Patent application EP 1338603 A and has avaluable inhibitory effect on the sodium-dependent glucose cotransporterSGLT, particularly SGLT2. The method of manufacture of the compound ofthe formula I as described therein does not yield a crystalline form.

A certain pharmaceutical activity is of course the basic prerequisite tobe fulfilled by a pharmaceutically active agent before same is approvedas a medicament on the market. However, there are a variety ofadditional requirements a pharmaceutically active agent has to complywith. These requirements are based on various parameters which areconnected with the nature of the active substance itself. Without beingrestrictive, examples of these parameters are the stability of theactive agent under various environmental conditions, its stabilityduring production of the pharmaceutical formulation and the stability ofthe active agent in the final medicament compositions. Thepharmaceutically active substance used for preparing the pharmaceuticalcompositions should be as pure as possible and its stability inlong-term storage must be guaranteed under various environmentalconditions.

This is essential to prevent the use of pharmaceutical compositionswhich contain, in addition to the actual active substance, breakdownproducts thereof, for example. In such cases the content of activesubstance in the medicament might be less than that specified.

Uniform distribution of the medicament in the formulation is a criticalfactor, particularly when the medicament has to be given in low doses.To ensure uniform distribution, the particle size of the activesubstance can be reduced to a suitable level, e.g. by grinding. Sincebreakdown of the pharmaceutically active substance as a side effect ofthe grinding (or micronising) has to be avoided as far as possible, inspite of the hard conditions required during the process, it isessential that the active substance should be highly stable throughoutthe grinding process. Only if the active substance is sufficientlystable during the grinding process it is possible to produce ahomogeneous pharmaceutical formulation which always contains thespecified amount of active substance in a reproducible manner.

Another problem which may arise in the grinding process for preparingthe desired pharmaceutical formulation is the input of energy caused bythis process and the stress on the surface of the crystals. This may incertain circumstances lead to polymorphous changes, to amorphization orto a change in the crystal lattice. Since the pharmaceutical quality ofa pharmaceutical formulation requires that the active substance shouldalways have the same crystalline morphology, the stability andproperties of the crystalline active substance are subject to stringentrequirements from this point of view as well.

The stability of a pharmaceutically active substance is also importantin pharmaceutical compositions for determining the shelf life of theparticular medicament; the shelf life is the length of time during whichthe medicament can be administered without any risk. High stability of amedicament in the abovementioned pharmaceutical compositions undervarious storage conditions is therefore an additional advantage for boththe patient and the manufacturer.

The absorption of moisture reduces the content of pharmaceuticallyactive substance as a result of the increased weight caused by theuptake of water. Pharmaceutical compositions with a tendency to absorbmoisture have to be protected from moisture during storage, e.g. by theaddition of suitable drying agents or by storing the drug in anenvironment where it is protected from moisture. Preferably, therefore,a pharmaceutically active substance should be only slightly hygroscopic.

Furthermore, the availability of a well-defined crystalline form allowsthe purification of the drug substance by recrystallization.

Apart from the requirements indicated above, it should be generallyborne in mind that any change to the solid state of a pharmaceuticalcomposition which is capable of improving its physical and chemicalstability gives a significant advantage over less stable forms of thesame medicament.

The aim of the invention is thus to provide a new, stable crystallineform of the compound of the formula I which meets important requirementsimposed on pharmaceutically active substances as mentioned above.

OBJECT OF THE INVENTION

In a first aspect the present invention relates to a crystalline form ofthe compound of the formula I.

In a second aspect the present invention relates to the crystalline formof the compound of the formula I having an X-ray powder diffractionpattern that comprises peaks at 5.35, 10.76 and 16.20 degrees 2Θ (±0.05degrees 2Θ), wherein said X-ray powder diffraction pattern is made usingCuK_(α1) radiation.

In a third aspect the present invention relates to the compound of theformula I wherein at least 50% of said substance is present in the formof a crystalline form as defined hereinbefore and hereinafter.

In a fourth aspect the present invention relates to a pharmaceuticalcomposition or medicament comprising a crystalline form as definedhereinbefore and hereinafter.

In a fifth aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for inhibiting the sodium-dependent glucosecotransporter SGLT2.

In a sixth aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition which is suitable for the treatment orprevention of diseases or conditions which can be influenced byinhibiting sodium-dependent glucose cotransporter SGLT, preferablySGLT2.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for preventing, slowing progression of,delaying or treating a metabolic disorder selected from the groupconsisting of type 1 diabetes mellitus, type 2 diabetes mellitus,impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia,overweight, obesity, including class I obesity, class II obesity, classIII obesity, visceral obesity and abdominal obesity, and metabolicsyndrome in a patient in need thereof.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for improving glycemic control and/or forreducing of lasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patient in need thereof.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for preventing, slowing progression of,delaying or treating of a condition or disorder selected from the groupconsisting of complications of diabetes mellitus such as cataracts andmicro- and macrovascular diseases, such as nephropathy, retinopathy,neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction,stroke and peripheral arterial occlusive disease, in a patient in needthereof.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for preventing, slowing, delaying orreversing progression from impaired glucose tolerance, insulinresistance and/or from metabolic syndrome to type 2 diabetes mellitus ina patient in need thereof.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for reducing the weight or preventing anincrease of the weight or facilitating a reduction of the weight in apatient in need thereof.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for preventing, slowing, delaying or treatingthe degeneration of pancreatic beta cells and/or the decline of thefunctionality of pancreatic beta cells and/or for improving and/orrestoring the functionality of pancreatic beta cells and/or restoringthe functionality of pancreatic insulin secretion in a patient in needthereof.

In a further aspect the present invention relates to a use of acrystalline form as defined hereinbefore or hereinafter for preparing apharmaceutical composition for maintaining and/or improving the insulinsensitivity and/or for treating or preventing hyperinsulinemia and/orinsulin resistance in a patient in need thereof.

In a further aspect the present invention relates to a method for makinga crystalline form as defined hereinbefore and hereinafter, said methodcomprising the following steps:

-   (a) dissolving the compound of the formula I in a solvent or a    mixture of solvents to form a solution, preferably a saturated,    nearly saturated or supersaturated solution, with the proviso that    the starting material of said compound of the formula I and/or said    solvent or mixture of solvents contain an amount of H₂O which is at    least the quantity required to form a hemi-hydrate of the compound    of the formula I;-   (b) storing preferably with cooling the solution to precipitate the    crystalline form out of solution and thus to yield a suspension;-   (c) isolating the precipitate from the suspension; and-   (d) drying the precipitate optionally until any excess of said    solvent or mixture of solvents has been removed.

Yet further aspects of the present invention become apparent to the oneskilled in the art from the following detailed description of theinvention and the examples.

BRIEF DESCRIPTION OF THE FIGURES

The FIG. 1 shows an X-ray powder diffractogram of the crystalline formaccording to this invention.

The FIG. 2 shows the thermoanalysis and determination of the meltingpoint via DSC and of the weight loss via TG of the crystalline form.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that there exists a crystalline form ofthe compound of the formula I which fulfils important requirementsmentioned hereinbefore.

Moreover it has been found that the crystalline form according to thisinvention meets the stringent requirements mentioned above and thussolves the problem on which the present invention is based. Accordinglythe present invention relates to a crystalline form, in particular to acrystalline hydrate of the compound the formula I.

The crystalline form may be identified and distinguished from othercrystalline forms by means of their characteristic X-ray powderdiffraction (XRPD) patterns.

The crystalline form, in particular the crystalline hydrate, ischaracterised by an X-ray powder diffraction pattern that comprisespeaks at 5.35, 10.76 and 16.20 degrees 2Θ (±0.05 degrees 2Θ), whereinsaid X-ray powder diffraction pattern is made using CuK_(α1) radiation.

In particular said X-ray powder diffraction pattern comprises peaks at5,35, 9.31, 10.76, 16.20 and 19.81 degrees 2Θ (±0.05 degrees 2Θ),wherein said X-ray powder diffraction pattern is made using CuK_(α1)radiation.

In particular said X-ray powder diffraction pattern comprises peaks at5.35, 9.31, 10.76, 14.27, 16.20, 18.25, 19.81 and 23.27 degrees 2Θ(±0.05 degrees 2Θ), wherein said X-ray powder diffraction pattern ismade using CuK_(α1) radiation.

More specifically, the crystalline form, in particular the crystallinehydrate, is characterised by an X-ray powder diffraction pattern, madeusing CuK_(α1) radiation, which comprises peaks at degrees 2Θ (±0.05degrees 2Θ) as contained in Table 1.

TABLE 1 X-ray powder diffraction pattern of the crystalline form (onlypeaks up to 30° in 2 Θ are listed): 2 Θ d-value Intensity I/I₀ [°] [Å][%] 5.35 16.49 100 9.31 9.49 27 10.76 8.21 29 14.27 6.20 20 16.20 5.4733 16.56 5.35 15 18.25 4.86 22 18.73 4.73 12 19.52 4.54 15 19.81 4.48 2420.57 4.31 10 21.25 4.18 19 21.69 4.09 9 22.14 4.01 8 22.65 3.92 1023.27 3.82 20 23.64 3.76 10 25.11 3.54 15 26.32 3.38 10 27.42 3.25 8

Even more specifically, the crystalline form is characterised by anX-ray powder diffraction pattern, made using CuK_(α1) radiation, whichcomprises peaks at degrees 2Θ (±0.05 degrees 2Θ) as shown in FIG. 1.

Furthermore the crystalline form of the compound of the formula I ischaracterised by a melting point of about 109° C.±5° C. (determined viaDSC; evaluated at onset-temperature; heating rate 10 K/min). Theobtained DSC curve is shown in FIG. 2.

The crystalline form of the compound of the formula I is alsocharacterised by thermal gravimetry (TG) with a weight loss between 1.9and 2.9% of water up to the melting point at approximately 100° C. asdepicted by the dotted line in FIG. 2. The loss of water is alsoindicated by the endothermic peak of the solid DSC curve between about40 and 100° C. in the DSC diagram as shown in FIG. 2. The observedweight loss indicates that the crystalline form represents a crystallinehydrate form. In particular the crystalline hydrate form has astoichiometry close to a hemihydrate. In particular the content of waterlies in the range from about 0.5 to 0.7 mol per mol of the compound ofthe formula I.

The X-ray powder diffraction patterns are recorded, within the scope ofthe present invention, using a STOE-STADI P-difractometer intransmission mode fitted with a location-sensitive detector (OED) and aCu-anode as X-ray source (CuK_(α1) radiation, λ=1.54056 Å, 40 kV, 40mA). In the Table 1 above the values “2Θ [°]” denote the angle ofdiffraction in degrees and the values “d [Å]” denote the specifieddistances in Å between the lattice planes. The intensity shown in theFIG. 1 is given in units of cps (counts per second).

In order to allow for experimental error, the above described 2Θ valuesshould be considered accurate to ±0.05 degrees 2Θ. That is to say, whenassessing whether a given sample of crystals of the compound of theformula I is the crystalline form in accordance with the invention, a 2Θvalue which is experimentally observed for the sample should beconsidered identical with a characteristic value described above if itfalls within ±0.05 degrees 2Θ of the characteristic value.

The melting points are determined by DSC (DifferentialScanning-Calorimetry) using a DSC 821 (Mettler Toledo). The weight losswas determined by thermal gravimetry (TG) using a TGA 851 (MettlerToledo).

A further aspect of the present invention relates to a method for makingthe crystalline form of the compound of the formula I as definedhereinbefore and hereinafter, said method comprising the followingsteps:

-   (a) dissolving the compound of the formula I in a solvent or a    mixture of solvents to form a solution, preferably a saturated,    nearly saturated or supersaturated solution, with the proviso that    said compound of the formula I and/or said solvent or mixture of    solvents contain an amount of H₂O which is at least the quantity    required to form a hemi-hydrate of the compound of the formula I;-   (b) storing the solution to precipitate the crystalline form out of    solution and thus to yield a suspension;-   (c) isolating the precipitate from the suspension; and-   (d) drying the precipitate optionally until any excess of said    solvent or mixture of solvents has been removed.

The terms “saturated” or “nearly saturated” or “supersaturated” arerelated to the starting material of the compound of the formula I asused in step (a). For example a solution which is saturated or nearlysaturated with respect to the starting material of the compound of theformula I may be supersaturated with respect to its crystalline form.

Suitable solvents are preferably selected from the group consisting ofC₁₋₄-alkanols, cyclic ethers, esters, acetonitrile, mixtures of two ormore of these solvents and mixtures of one or more of these solventswith water.

More preferred solvents are selected from the group consisting ofmethanol, ethanol, i-propanol, tetrahydrofuran (THF), dioxane,butylacetate, acetonitrile, mixtures of two or more of these solventsand mixtures of one or more of these solvents with water.

Particularly preferred solvents are selected from the group consistingof ethanol, tetrahydrofuran, n-butylacetate and mixtures of one or moreof such solvents with water.

Water itself may also serve as the only solvent in step (a).

The amount of solvent or mixture of solvents is preferably chosen toobtain a saturated or nearly saturated solution. In case tetrahydrofuranis taken as solvent, the amount of tetrahydrofuran is preferably in therange from about 0.1 L to 1 L of tetrahydrofuran per mol of compound ofthe formula I; even more preferably in the range from about 0.2 to 0.8L; most preferably from about 0.25 to 0.6 L per mol of compound of theformula I.

The proviso for the starting material of the compound of the formula Iand/or the solvent and mixtures of solvents is that these contain anamount of H₂O which is at least the quantity required to form ahemihydrate of the compound of the formula I; in particular at least 0.5to 0.7 mol of water per mol of compound of the formula I. Preferably theamount of water is in the range from about 0.5 to 5.0 mol of water permol of compound of the formula I; even more preferably in the range fromabout 1 to 4 mol of water per mol of compound of the formula I, mostpreferably in the range from about 1.5 to 3.0 mol of water per mol ofcompound of the formula I, for example about 2 mol of water. This meansthat either the compound of the formula I as starting material or saidsolvent or mixture of solvents, or the compound of the formula Itogether with said solvent or mixture of solvents contain an amount ofH₂O as specified above. For example if the starting material of thecompound of the formula I in step (a) does contain sufficient water asspecified above, a water content of the solvent(s) is not mandatory.

Preferably the solvent or mixture of solvents (other than water) areadded to the compound of the formula I (or vice versa) to yield asolution and then the amount of water is added.

Preferably the step (a) is carried at about room temperature (about 20°C.) or at an elevated temperature up to about the boiling point of thesolvent or mixture of solvents used. A preferred temperature range isbetween about 35° C. and 100° C., even more preferably from about 45° C.to 80° C.

In step (b) the solution is stored for a time sufficient to obtain aprecipitate. The temperature of the solution in step (b) is preferablyabout the same as or lower than in step (a). During storage thetemperature of the solution containing the compound of the formula I ispreferably lowered, preferably to a temperature in the range from −10°C. to 25° C. or even lower, even more preferably in the range from −5 to15° C. Step (b) can be carried out with or without stirring. As known tothe one skilled in the art by varying the period of time and thedifference of temperature in step (b) the size, shape and quality of theobtained crystals can be controlled. Furthermore the crystallization maybe induced by methods known in the art, for example by mechanical meanssuch as scratching or rubbing the contact surface of the reaction vesselwith e.g. a glass rod. Optionally the saturated or supersaturatedsolution may be inoculated with seed crystals.

In order to reduce the solubility of the compound of the formula I inthe solution, in step (a) and/or in step (b) one or more antisolventsmay be added, preferably during step (a) or at the beginning of step(b). Suitable antisolvents may be selected from the group consisting ofethers, alkanes, cycloalkanes and mixtures thereof, in particularaliphatic ethers, C₆₋₈-alkanes, C₆₋₈-cycloalkanes and mixtures thereof.Examples of antisolvents or non-solvents are diisopropylether,tert-butylmethylether (TBME), cyclohexane, methylcyclohexane, hexane,heptane, octane and mixtures thereof, preferably tert-butylmethylether(TBME).

The amount of antisolvent is preferably chosen to obtain asupersaturated or nearly supersaturated solution. In case TBME is takenas an antisolvent, the amount of TBME is preferably in the range fromabout 2 L to 20 L of TBME per liter of solvent, in particular of THF assolvent; even more preferably in the range from about 4 to 15 L; mostpreferably from about 5 to 10 L per liter of solvent, in particular ofTHF as solvent.

In step (c) the solvent(s) can be removed from the precipitate by knownmethods as for example filtration, suction filtration. decantation orcentrifugation.

In step (d) an excess of the solvent(s) is optionally removed from theprecipitate by methods known to the one skilled in the art as forexample by reducing the partial pressure of the solvent(s), preferablyin vacuum, and/or by heating from above room temperature (ca. 20° C.),preferably in a temperature range below 70° C., even more preferablybelow 50° C., most preferably below 40° C.

During the drying process at elevated temperatures, for example attemperatures of about 50° C. or above, at least some amount of waterbound in the crystalline form may also be removed. As this process isreversible, storing of the substance at normal conditions, for exampleat room temperature (approx. 20° C.) and a relative humidity of 30 to60%, preferably in a humid environment, for example at a relativehumidity of equal to or greater than 80%, may yield a crystalline formaccording to this invention again.

The compound of the formula I may be synthesized by methods asspecifically and/or generally described or cited in the European patentapplication EP 1338603 A. Furthermore the biological properties of thecompound of the formula I may be investigated as it is described in saidEuropean patent application.

A crystalline form in accordance with the invention is preferablyemployed as drug active substance in substantially pure form, that is tosay, essentially free of other crystalline forms of the compound of theformula I. Nevertheless, the invention also embraces the crystallineform according to this invention in admixture with another crystallineform or forms. Should the drug active substance be a mixture ofcrystalline forms, it is preferred that the substance comprises at least50% of the crystalline form as described herein.

In view of the ability to inhibit the SGLT activity, a crystalline formaccording to the invention is suitable for the preparation ofpharmaceutical compositions for the treatment and/or preventativetreatment of all those conditions or diseases which may be affected bythe inhibition of the SGLT activity, particularly the SGLT-2 activity,for example for the treatment and/or preventive treatment of one or moremetabolic disorders.

Therefore, a crystalline form according to this invention isparticularly suitable for the preparation of pharmaceutical compositionsfor preventing, slowing progression of, delaying or treating a metabolicdisorder selected from the group consisting of type 1 diabetes mellitus,type 2 diabetes mellitus, impaired glucose tolerance, hyperglycemia,postprandial hyperglycemia, overweight, obesity, including class Iobesity, class II obesity, class III obesity, visceral obesity andabdominal obesity, and metabolic syndrome in a patient in need thereof.

Furthermore a crystalline form according to this invention isparticularly suitable for the preparation of pharmaceutical compositionsfor improving glycemic control and/or for reducing of fasting plasmaglucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c in a patient in need thereof.

As by a use of the crystalline form according to this invention animprovement of the glycemic control in patients in need thereof isobtainable, also those conditions and/or diseases related to or causedby an increased blood glucose level may be treated.

Therefore a crystalline form according to this invention is particularlysuitable for the preparation of pharmaceutical compositions forpreventing, slowing progression of, delaying or treating of a conditionor disorder selected from the group consisting of complications ofdiabetes mellitus such as cataracts and micro- and macrovasculardiseases, such as nephropathy, retinopathy, neuropathy, tissueischaemia, arteriosclerosis, myocardial infarction, stroke andperipheral arterial occlusive disease, in a patient in need thereof. Theterm “tissue ischaemia” particularly comprises diabetic macroangiopathy,diabetic microangiopathy, impaired wound healing and diabetic ulcer.

A crystalline form according to this invention may also have valuabledisease-modifying properties with respect to diseases or conditionsrelated to impaired glucose tolerance, insulin resistance and/ormetabolic syndrome.

Therefore in another aspect a crystalline form according to thisinvention is particularly suitable for the preparation of pharmaceuticalcompositions for preventing, slowing, delaying or reversing progressionfrom impaired glucose tolerance, insulin resistance and/or frommetabolic syndrome to type 2 diabetes mellitus in a patient in needthereof.

By the administration of a pharmaceutical composition according to thisinvention excessive blood glucose levels are not converted to insolublestorage forms, like fat, but excreted through the urine of the patient.Therefore no gain in weight or even a reduction of the weight is theresult.

Following this a crystalline form according to this invention is alsoparticularly suitable for the preparation of pharmaceutical compositionsfor reducing the weight or preventing an increase of the weight orfacilitating a reduction of the weight in a patient in need thereof.

The pharmacological effect of a crystalline form according to thisinvention is independent of insulin. Therefore an improvement of theglycemic control is possible without an additional strain on thepancreatic beta cells. By an administration of a pharmaceuticalcomposition according to this invention a beta-cell degeneration and adecline of beta-cell functionality such as for example apoptosis ornecrosis of pancreatic beta cells can be delayed or prevented.Furthermore the functionality of pancreatic cells can be improved orrestored, and the number and size of pancreatic beta cells increased. Itmay be shown that the differentiation status and hyperplasia ofpancreatic beta-cells disturbed by hyperglycemia can be normalized bytreatment with a pharmaceutical composition according to this invention.

Therefore a crystalline form according to this invention is particularlysuitable for the preparation of pharmaceutical compositions forpreventing, slowing, delaying or treating the degeneration of pancreaticbeta cells and/or the decline of the functionality of pancreatic betacells and/or for improving and/or restoring the functionality ofpancreatic beta cells and/or restoring the functionality of pancreaticinsulin secretion in a patient in need thereof.

As a result a crystalline form according to this invention isparticularly suitable for the preparation of pharmaceutical compositionsfor maintaining and/or improving the insulin sensitivity and/or fortreating or preventing hyperinsulinemia and/or insulin resistance in apatient in need thereof.

In particular, a crystalline-form according to the invention is suitablefor the preparation of pharmaceutical compositions for the prevention ortreatment of diabetes, particularly type 1 and type 2 diabetes mellitus,and/or diabetic complications.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans,but the crystalline form may also be used accordingly in veterinarymedicine on mammals.

Within the scope of the present invention the pharmaceutical compositioncomprising a crystalline form according to this invention is preferablyadministered orally. Other forms of administration are possible anddescribed hereinafter. Furthermore the treatment and/or prophylaxis, inthe following called therapy, according to this invention is preferablya monotherapy, i.e. during the time of the therapy preferably no otherantidiabetic drug other than the crystalline form according to thisinvention is given to the patient.

As described hereinbefore by the administration of a pharmaceuticalcomposition according to this invention excessive blood glucose isexcreted through the urine of the patient, so that no gain in weight oreven a reduction of the weight may result. Therefore a treatment orprophylaxis according to this invention is advantageously suitable inthose patients in need of such treatment or prophylaxis who arediagnosed of one or more of the conditions selected from the groupconsisting of overweight, class I obesity, class II obesity, class IIIobesity, visceral obesity and abdominal obesity or for those individualsin which a weight increase is contraindicated.

It is found that the crystalline form according to this inventionexhibits a very good efficacy with regard to glycemic control, inparticular in view of a reduction of fasting plasma glucose,postprandial plasma glucose and/or glycosylated hemoglobin (HbA1c). Byadministering a pharmaceutical composition according to this invention areduction of HbA1c equal to or greater than preferably 0.5%, even morepreferably equal to or greater than 1.0% can be achieved and thereduction is particularly in the range from 1.0% to 1.5%.

Furthermore the methods according to this invention is advantageouslyapplicable in those patients who show one, two or more of the followingconditions:

-   (a) a fasting blood glucose or serum glucose concentration greater    than 110 mg/dL, in particular greater than 125 mg/dL;-   (b) a postprandial plasma glucose equal to or greater than 140    mg/dL;-   (c) an HbA1c value equal to or greater than 6.5%, in particular    equal to or greater than 8.0%.

The present invention also discloses the use of a pharmaceuticalcomposition according to this invention for improving glycemic controlin patents having type 2 diabetes or showing first signs of prediabetes.Thus, the invention also includes diabetes prevention. If therefore acrystalline form according to this invention is used immediately toimprove the glycemic control as soon as one of the above-mentioned signsof prediabetes is present, the onset of manifest type 2 diabetesmellitus can be delayed or prevented.

Furthermore a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients with insulindependency, i.e. in patients who are treated or otherwise would betreated or need treatment with an insulin or a derivative of insulin ora substitute of insulin or a formulation comprising an insulin or aderivative or substitute thereof. These patients include patients withdiabetes type 2 and patients with diabetes type 1.

It can be found that by using a pharmaceutical composition according tothis invention an improvement of the glycemic control can be achievedeven in those patients who have insufficient glycemic control inparticular despite treatment with one or more antidiabetic drugs, forexample despite maximal tolerated dose of oral monotherapy with eithermetformin or an antidiabetic of the class of sulphonylureas. A maximaltolerated dose with regard to metformin is for example 850 mg threetimes a day or any equivalent thereof. In the scope of the presentinvention the term “insufficient glycemic control” means a conditionwherein patients show HbA1c values above 6.5%, in particular above 8%.

Therefore according to a preferred embodiment of the present inventionthere is provided a method for improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patent in need thereof whois diagnosed with impaired glucose tolerance, with insulin resistance,with metabolic syndrome and/or with type 2 or type 1 diabetes mellituscharacterized in that a pharmaceutical composition comprising acrystalline form according to this invention is administered.

It is found that the lowering of the blood glucose level by theadministration of a pharmaceutical composition according to thisinvention is insulin-independent. Therefore a crystalline form accordingto this invention is particularly suitable in the treatment of patientswho are diagnosed having one or more of the following conditions

-   -   insulin resistance,    -   hyperinsulinemia,    -   pre-diabetes,    -   type 2 diabetes mellitus, particular having a late stage type 2        diabetes mellitus,    -   type 1 diabetes mellitus.

Furthermore a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   (a) obesity (including class I, II and/or III obesity), visceral    obesity and/or abdominal obesity,-   (b) triglyceride blood level ≧150 mg/dL,-   (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50    mg/dL in male patients,-   (d) a systolic blood pressure ≧130 mm Hg and a diastolic blood    pressure ≧85 mm Hg,-   (e) a fasting blood glucose level ≧110 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance,with insulin resistance and/or with metabolic syndrome suffer from anincreased risk of developing a cardiovascular disease, such as forexample myocardial infarction, coronary heart disease, heartinsufficiency, thromboembolic events. A glycemic control according tothis invention may result in a reduction of the cardiovascular risks.

A pharmaceutical composition according to this invention exhibits a goodsafety profile. Therefore a treatment or prophylaxis according to thisinvention is advantageous possible in those patients for which thetreatment with other antidiabetic drugs, such as for example metformin,is contraindicated and/or who have an intolerance against such drugs attherapeutic doses. In particular a treatment or prophylaxis according tothis invention is advantageous possible in those patients showing orhaving an increased risk for one or more of the following disorders:renal insufficiency or diseases, cardiac diseases, cardiac failure,hepatic diseases, pulmonal diseases, catabolytic states and/or danger oflactate acidosis, or female patients being pregnant or during lactation.

Furthermore it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no or in a low riskof hypoglycemia. Therefore a treatment or prophylaxis according to thisinvention is also advantageously possible in those patients showing orhaving an increased risk for hypoglycemia.

The pharmaceutical composition according to this invention isparticularly suitable in the long term treatment or prophylaxis of thediseases and/or conditions as described hereinbefore and hereinafter, inparticular in the long term glycemic control in patients with type 2diabetes mellitus.

The term “long term” as used hereinbefore and hereinafter indicates atreatment of or administration in a patient within a period of timelonger than 12 weeks, preferably longer than 25 weeks, even morepreferably longer than 1 year.

Therefore a particularly preferred embodiment of the present inventionprovides a method for oral therapy, preferably oral monotherapy, forimprovement, especially long term improvement, of glycemic control inpatients with type 2 diabetes mellitus, especially in patients with latestage type 2 diabetes mellitus, in particular in patients additionallydiagnosed of overweight, obesity (including class I, class II and/orclass III obesity), visceral obesity and/or abdominal obesity.

It will be appreciated that the amount of the crystalline form accordingto this invention to be administered to the patient and required for usein treatment or prophylaxis according to the present invention will varywith the route of administration, the nature and severity of thecondition for which treatment or prophylaxis is required, the age,weight and condition of the patient, concomitant medication and will beultimately at the discretion of the attendant physician. In generalhowever the crystalline form according to this invention is included inthe pharmaceutical composition or dosage form in an amount sufficient toimprove glycemic control in the patient to be treated.

The pharmaceutical composition to be administered to the patientaccording to a method as described hereinbefore and hereinafterpreferably comprises an amount in the range from 1 mg to 1000 mg, evenmore preferably from 10 to 500 mg, most preferably from 50 to 500 mg ofa crystalline form according to this invention per day with respect toan adult patient. The above specified amounts are especially preferredfor oral administration. An example of a suitable pharmaceuticalcomposition according to this invention is a tablet for oraladministration comprising 200 mg of a crystalline form according to thisinvention.

The desired dose of the pharmaceutical composition according to thisinvention may conveniently be presented in a single dose once daily oras divided dose administered at appropriate intervals, for example astwo, three or more doses per day.

The pharmaceutical composition is advantageously formulated for oraladministration in solid form. The formulations may, where appropriate,be conveniently presented in discrete dosage units and may be preparedby any of the methods well known in the art of pharmacy. All methodsinclude the step of bringing into association the active compound withfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets,granules, fine granules, powders, capsules, caplets, soft capsules,pills, dry syrups, chewable tablets, troches, effervescent tablets,suspension, fast dissolving tablets, oral fast-dispersing tablets, etc.

The pharmaceutical composition preferably comprises one or morepharmaceutical acceptable carriers. Such carriers are preferably“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions suitable for oral administration mayconveniently be presented as discrete units such as capsules, includingsoft gelatin capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a suspension or as an emulsion. Tablets and capsules for oraladministration may contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets may be coated according to methods well known in the art.

Examples of pharmaceutically acceptable carriers are known to the oneskilled in the art.

In the foregoing and in the following the terms as defined hereinafterare used:

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The term “obesity” is defined as the condition wherein the individualhas a BMI equal to or greater than 30 kg/m². According to a WHOdefinition the term obesity may be categorized as follows: the term“class I obesity” is the condition wherein the BMI is equal to orgreater than 30 kg/m² but lower than 35 kg/m²; the term “class IIobesity” is the condition wherein the BMI is equal to or greater than 35kg/m² but lower than 40 kg/m²; the term “class III obesity” is thecondition wherein the BMI is equal to or greater than 40 kg/m².

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference ≧85 cm in men and ≧90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 110 mg/dL (6.11 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 110 mg/dL (6.11 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L),

The term “impaired glucose tolerance” or “IGT”, is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration greater than 110 mg/dL and lessthan 126 mg/dl (7.00 mmol/L), or a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The term impaired glucose toleranceis also intended to apply to the condition of impaired fasting glucose.The abnormal glucose tolerance, i.e. the 2 hour postprandial bloodglucose or serum glucose concentration can be measured as the bloodsugar level in mg of glucose per dL of plasma 2 hours after taking 75 gof glucose after a fast.

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, in whichthe fasting or postprandial serum or plasma insulin concentration iselevated above that of normal, lean individuals without insulinresistance, having a waist-to-hip ration <1.0 (for men) or <0.8 (forwomen).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably,

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition), Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. In this method it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl. 1): A459) and to an euglycemic clamp study. In addition,plasma adiponectin levels can be monitored as a potential surrogate ofinsulin sensitivity. The estimate of insulin resistance by thehomeostasis assessment model (HOMA)-IR score is calculated with theformula (Galvin P. et al. Diabet Med 1992;9:921-8):HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patients triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Patients with a predisposition for the development of IGT or type 2diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detectedthis is a particularly strong indication of the presence of prediabetes.Thus, it may be that in order to maintain glucose homoeostasis a personneeds 2-3 times as much insulin as another person, without this havingany direct pathological significance.

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of the beta-cellfunction can be measured for example by determining a HOMA-index forbeta-cell function (Matthews at al., Diabetologia 1985, 28: 412-19), theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl. 1): A459), the insulin/C-peptide secretion after an oralglucose tolerance test or a meal tolerance test, or by employing ahyperglycemic clamp study and/or minimal modeling after a frequentlysampled intravenous glucose tolerance test (Stumvoll et al., Eur J ClinInvest 2001, 31: 380-81).

The term “pre-diabetes” is the condition wherein an individual ispre-disposed to the development of type 2 diabetes. Pre-diabetes extendsthe definition of impaired glucose tolerance to include individuals witha fasting blood glucose within the high normal range ≧100 mg/dL (J. B.Meigs, at al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia(elevated plasma insulin concentration). The scientific and medicalbasis for identifying pre-diabetes as a serious health threat is laidout in a Position Statement entitled “The Prevention or Delay of Type 2Diabetes” issued jointly by the American Diabetes Association and theNational Institute of Diabetes and Digestive and Kidney Diseases(Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two ormore of the following attributes 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or type 2 diabetes. Insulin resistance can beconfirmed in these individuals by calculating HOMA-IR score. For thepurpose of this invention, insulin resistance is defined as the clinicalcondition in which an individual has a HOMA-IR score >4.0 or a HOMA-IRscore above the upper limit of normal as defined for the laboratoryperforming the glucose and insulin assays.

The term “type 2 diabetes” is defined as the condition in which asubject has a fasting blood glucose or serum glucose concentrationgreater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucosevalues is a standard procedure in routine medical analysis. If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL of plasma 2 hours after 75 g ofglucose have been taken on an empty stomach. In a glucose tolerance test75 g of glucose are administered orally to the patient being testedafter 10-12 hours of fasting and the blood sugar level is recordedimmediately before taking the glucose and 1 and 2 hours after taking it.In a healthy subject the blood sugar level before taking the glucosewill be between 60 and 110 mg per dL of plasma, less than 200 mg per dL1 hour after taking the glucose and less than 140 mg per dL after 2hours. If after 2 hours the value is between 140 and 200 mg this isregarded as abnormal glucose tolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy,coronary heart disease (CHD).

The term “HbA1C” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain, its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1c value is not sufficient in all diabetics to achieve thedesired target range of <6.5% and preferably <6% HbA1c.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002;156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women: or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference ≧85 cm in men and ≧90 cm in women;    -   2. Triglycerides: ≧150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≧130/85 mm Hg (SBP ≧130 or DSP ≧85)    -   5. Fasting blood glucose ≧110 mg/dL.

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor und Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition hypertension is diagnosed if thesystolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolicblood pressure (DBP) exceeds a value of 90 mm Hg. If a patient issuffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The terms “prophylactically treating” and “preventing” are usedinterchangeably.

The following examples of synthesis serve to illustrate a method ofpreparing the compound of the formula I and its crystalline form. It isto be regarded only as a possible method described by way of example,without restricting the invention to its contents.

In the foregoing and following text, H atoms of hydroxyl groups are notexplicitly shown in every case in structural formulae. In case thepressure is indicated in the unit “bar”, the corresponding values can beconverted into SI units by using 1 bar=0.1 MPa. In case the pressure isindicated in the unit “psi”, the corresponding values can be convertedinto SI units by using 1 psi=6894.757 Pa. The following abbreviationsare used hereinbefore and hereinafter:

TBME tert-butylmethylether, THF tetrahydrofuran.

EXPERIMENTAL PROCEDURES Example 1 Synthesis of1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)-methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranoside(I)

Example 1.1 Preparation of 5-Methyl-3-pyrazolidinone monohydrochloride(VIII.1)

Ethyl crotonate (500 ml; 3.94 mol) is dissolved in isopropanol (1.85 L)and heated to 50° C. Hydrazine hydrate (215 ml; 4.34 mol) is addedwithin 30 min. and the reaction mixture is heated to reflux for 2 h. Thesolvent is then distilled off (approx. 1 L) under reduced pressure.Isopropanol (400 ml) is then added and the reaction mixture is cooled to22° C. Hydrochloric acid 11.7 N in ethanol (375 ml, 3.94 mol) is addedand the reaction mixture is stirred at about 20 to 25° C. 15 h. Thereaction mixture is then cooled to 0° C., filtered and the product iswashed with isopropanol (3 times with each 200 ml); then dried toconstant weight at 45° C. to yield colorless crystals. Mass and¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=101 [M+H]⁺

Example 1.2 Preparation of 1-(1-Methylethyl)-5-methyl-3-pyrazolidinonemonohydrochloride (VII.1a)

5-Methyl-3-pyrazolidinone monohydrochloride (692 g; 5.07 mol) issuspended in isopropanol (4.9 L). Aqueous 50% sodium hydroxide (270 ml;5.07 mol) and palladium (10%-weight) on charcoal (70 g) together withacetone (744 ml, 10 mol) are added. The mixture is then hydrogenatedunder an atmosphere of hydrogen at 50° C. 3 bar (42 psi) until uptake ofhydrogen ceases. The reaction mixture is filtered and solvent isdistilled off under reduced pressure.

The residue is treated two times with 1 L of isopropanol which issubsequently distilled off under reduced pressure. The remainder isdissolved in isopropanol (3.5 L) and filtered. To the filtrate is addedhydrogen chloride 10.5N in ethanol (482 ml: 5.06 mol) which causes theprecipitation of the hydrochloride salt which is isolated by filtration.It is washed two times with isopropanol (2×500 ml) and dried at 45° C.to yield the product as colourless crystals.

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=143 [M+H]⁺

Example 1.3 Preparation of 1-(1-methylethyl)-5-methyl-3-pyrazolidinone(VII.1)

1-(1-Methylethyl)-5-methyl-3-pyrazolidinone monohydrochloride (150 g;0.84 mol) is treated with saturated aqueous potassium carbonate (1.2 L)and ethyl acetate (1.0 L). The mixture is filtered and the phases areseparated. The organic phase is dried with anhydrous sodium sulphate,filtered and evaporated in vacuo to yield1-(1-methylethyl)-5-methyl-3-pyrazolidinone as a solid.

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=143 [M+H]⁺

Example 1.4 Preparation of1,2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazol-3-one (VI.1)

1-(1-methylethyl)-5-methyl-3-pyrazolidinone (390 g; 2.74 mol) isdissolved in acetic acid (170 ml) with warming. 35% aqueous hydrogenperoxide (260 ml; 3.0 mol) is added within 3 h while keeping thetemperature at about 65° C. The reaction mixture is then stirred atabout 20 to 25° C. for 15 h. Water (1.2 L) is then added and the pH ofthe mixture is adjusted to about 7 by means of addition of approx. 1 L50%-weight aqueous sodium hydroxide solution. Upon cooling to 5° C. thereaction mixture is filtered. The product is washed with water and driedat about 50° C. Colourless crystals are obtained.

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=141 [M+H]⁺

Example 1.51,2-Dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)-(ethoxy)methyl]-5-methyl-3H-pyrazol-3-one(IV.1)

Pyrrolidine (21 ml; 0.257 mol) and acetic acid (22 ml; 0.385 mol) areadded to a mixture of1,2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazol-3-one (180 g; 1.28mol) and 2-fluoro-4-methoxybenzaldehyde (198 g; 1.28 mol) in ethanol(2.7 L). The suspension is heated to about 50° C. for about 67 h. Thereaction mixture is then cooled to approx. 17° C. and filtered. Theproduct is washed with diisopropyl ether (500 ml) and subsequentlyrefluxed with THF (2.5 L). The obtained solution is filtered over a padof Celite and charcoal. The filtrate is concentrated in vacuo and water(2 L) is added to the suspension which is cooled and filtered. Thecolourless crystals are dried at 50° C.

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=323 [M+H]⁺

Example 1.61,2-Dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one(III.1)

A mixture of1,2-dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)-(ethoxy)methyl]-5-methyl-3H-pyrazol-3-one(294 g; 1.28 mol), methanol (4.5 L), aqueous hydrochloric acid (30%; 11g) and water (80 mL) is hydrogenated with palladium on charcoal(10%-weight) (65 g) at 50° C. and 3 bar hydrogen pressure until hydrogenuptake ceases. THF (2.3 L) is added to the reaction mixture which isthen filtered. The catalyst is washed with THF (1 L) and the solvent isdistilled off under reduced pressure to a residual volume of approx. 700to 800 ml. The resulting suspension is poured into water (1 L) withstirring. The precipitate is isolated by filtration, washed with water(400 ml) and dried at 55° C. to yield crystals (light beige).

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺), m/z=279 [M+H]⁺

Example 1.7 2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (II.1)

1,2,3,4,6-Penta-O-acetyl-β-D-glucopyranose (100 g, 0.251 mol) issuspended in toluene (210 ml), Acetic anhydride (9.5 ml; 0.1 mol) isadded followed by hydrobromic acid 30% in acetic acid (200 ml, 1 ml).The mixture is stirred at 18° C. for 30 min. A mixture of ice water.(300 ml) and brine (100 ml) is then added with stirring. The phases areseparated and the aqueous phase is extracted with toluene (100 ml). Theorganic phases are combined and washed with aqueous sodiumhydrogencarbonate (100 ml) and brine (100 ml). Drying and evaporation ofthe solvent under reduced pressure yields an oil which is crystallisedby addition of methyl-t-butylether (150 ml) and methylcyclohexane (300ml). The product is isolated by filtration, washed withmethylcyclohexane and dried under vacuo at 45° C.

Example 1.81′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-(2,3,4,6-O-tetraacetyl)-β-D-glucopyranoside(I.1)

Aqueous potassium hydroxide (1M; 870 ml) is added to a mixture of(2,3,4,6-O-tetraacetyl)-α-D-glucopyranosyl bromide (485 g; 1.169 mol),1,2-dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one(161 g, 0.58 mol) and tetrabutylammonium chloride (9.4 g; 0.029 mol) indichloromethane (780 L). The two phase mixture is vigorously stirred at25 to 27° C. while the pH of the aqueous layer is kept constant atapprox. 13 by adding further aqueous potassium hydroxide (4N; about 870ml) until consumption of base ceases (about 5 h). The progress of thereaction can be monitored by HPLC. The phases are then separated and theaqueous phase is extracted with dichloromethane (800 ml). The combinedorganic phases are dried (Na₂SO₄), filtered and evaporated under reducedpressure to yield an oil (yellow). This is used in the next reactionstep without further purification.

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=609 [M+H]⁺

Example 1.91′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranoside(I)

Crude1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-(2,3,4,6-O-tetraacetyl)-β-D-glucopyranoside(413 g; approx. 0.58 mol) of the previous reaction is dissolved in dryethanol (1 L). Potassium-t-butoxide (6.6 g; 0.058 mol) is then added andthe reaction mixture is stirred at about 20 to 25° C. for approx. 15 h.Acetic acid (3.3 ml; 0.058 mol) is then added and the solvent isdistilled off under reduced pressure. The resulting residue is thendissolved in ethyl acetate (2 L) and washed with brine (800 ml). Theorganic phase is separated, dried over Na₂SO₄, filtered and evaporatedunder reduced pressure to yield a resinous solid.

Mass and ¹H-NMR-spectra are in accordance with the assigned structure.

Mass spectrum (ESI⁺): m/z=441 [M+H]⁺

Example 2 Preparation of the Crystalline Form

As described hereinbefore during the drying process at elevatedtemperatures, for example at temperatures of about 50° C. or above, anddepending on the conditions during the drying process, like low relativehumidity, at least some amount of water bound in the crystalline formmay also be removed. As this process is reversible, storing of thesubstance at normal conditions, preferably in a humid environment, forexample at a relative humidity above 30% or between 30 and 60%, yields ahydrate according to this invention again.

Example 2.1

21.9 g of resinous or foamy4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1′-(1-methylethyl)-1H-pyrazol-3′-O-β-D-glucopyranosideis dissolved in ethanol. The solvent is distilled off under reducedpressure just to the point of beginning of foaming. The resulting thick,clear syrup is dissolved in water (75 ml) at about 20° C. andcrystallisation is induced by scratching with a glass rod. The processof crystallisation is completed by stirring the suspension atapproximately 20° C. for approx. 16 h. The product is isolated byfiltration, washed with cold water, dried first at approximately 20° C.in a desiccator (NaOH pellets) and finally at about 40° C. to yieldcolourless crystals.

Example 2.2

27.80 g of resinous4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1′-(1-methylethyl)-1H-pyrazol-3′-O-β-D-glucopyranosideis dissolved in THF (28 mL). TBME (190 mL) and water (1 mL) are addedand the mixture is heated to reflux. The hot solution is filtered and inthe filtrate crystallization is induced by scratching with a glass rodor by inocculating with seed crystals. Crystallisation is completed bystirring at approximately 20° C. for 15 h. The product is isolated byfiltration, washed with TBME and dried at 40 to 50° C.

Example 2.3

16 mL THF is added to 28 g of resinous4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1′-(1-methylethyl)-1H-pyrazol-3′-O-β-D-glucopyranoside.TBME (100 mL) is added and the mixture is warmed to 50° C. Water (1.1mL) and further TBME (120 mL) are added at 50° C. to the clear solution.The hot solution is then seeded and cooled to 30° C. within 1 h.Alternatively crystallization may be induced by scratching with a glassrod for example. The resulting thick suspension is further cooled toapprox. 0° C. and is stirred at this temperature for 2.5 h. It is thenfiltered, washed with cold TBME and dried at 45° C. to yield acrystalline product.

Example 2.4

28 g resinous4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1′-(1-methylethyl)-1H-pyrazol-3′-O-β-D-glucopyranosideis dissolved in a mixture of THF (26 ml) and water (2.1 ml) at 60° C.TBME (150 mL) is added and the hot mixture is filtered. Insolubles arewashed with TBME (50 ml). The combined turbid filtrate is again heatedand the resulting solution is seeded and cooled to room temperature(approx. 20° C.) within 1.5 h. Instead of using seed crystalscrystallization may be started by scratching with a glass rod forexample. The resulting thick suspension is further cooled to 0° C. andstirred for 1.5 h before filtering. The product is washed with TBME (30ml) and is finally dried at 40° C. to yield colourless crystals.

Example 2.5

33 g resinous4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1′-(1′-methylethyl)-1H-pyrazol-3′-O-β-D-glucopyranosideis dissolved in 150 ml n-butyl acetate at approx. 80° C. The solution isfiltered over charcoal which is washed with further hot 50 ml n-butylacetate. Water (2.1 ml) is added to the combined warm filtrates at 30°C. The solution is seeded and stirred at 0° C. for 16 h, 300 ml TBME areadded to the resulting suspension within 10 minutes. The mixture iscooled to −6° C. and stirred for 1 h before filtering. The solid iswashed with TBME (200 ml) and is then dried at 50° C. over night toyield colourless crystals.

1. Crystalline form of1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranosidehaving an X-ray powder diffraction pattern that comprises peaks at 5.35,10.76 and 16.20 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powderdiffraction pattern is made using CuK_(α1) radiation.
 2. Crystallineform according to claim 1 wherein the X-ray powder diffraction patternfurther comprises peaks at 9.31 and 19.81 degrees 2Θ (±0.1 degrees 2Θ),wherein said X-ray powder diffraction pattern is made using CuK_(α1)radiation.
 3. Crystalline form according to claim 1, wherein the X-raypowder diffraction pattern further comprises peaks at 14.27, 18.25 and23.27 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powderdiffraction pattern is made using CuK_(α1) radiation.
 4. Crystallineform according to claim 1, characterized in that it comprises water inthe range from 0 to 10 weight-%. 5.1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-β-D-glucopyranosidewherein at least 50% by weight of said substance is present in the formof a crystalline form in accordance with claim
 1. 6. A pharmaceuticalcomposition comprising a crystalline form according to claim
 1. 7. Amethod for making a crystalline form in accordance with claim 1 saidmethod comprising the following steps: (a) dissolving the compound ofthe formula I

in a solvent or a mixture of solvents to form a solution; (b) storingthe solution to precipitate the crystalline form out of solution andthus to yield a suspension; (c) isolating the precipitate from thesuspension; and (d) drying the precipitate optionally until an excess ofsaid solvent or mixture of solvents has been removed.
 8. The methodaccording to claim 7, wherein in step (a) and/or step (b) one or moreantisolvents are added.
 9. The method according to claim 7, wherein thestaining material of the compound of the formula I and/or said solventor mixture of solvents contain at least an amount of 0.5 mol H₂O per molof the compound of the formula I.
 10. Crystalline form according toclaim 4, characterized by a content of water in the range from about 0.5to 4.0 weight-% at a relative humidity between 30 and 50%.